Novartis’s Biosimilar of Neupogen Clears a Big Hurdle, But Major Issues Remain for it and Other Biosimilars

FDA’s Oncologic Drugs Advisory Committee unanimously voted in favor of approval of EP2006, Novartis’s biosimilar version of Amgen’s Neupogen® (filgrastim) for all five of the indications for which Neupogen is approved. This ground-breaking event manages to both move the US a little closer to the long-awaited first approval of a BPCIA biosimilar and to highlight the challenges biosimilars have overcome and the open issues they still face before winning FDA approval, launching and gaining market acceptance. Among those issues are what the generic names will be, the standard for interchangeability and the applicability of the patent dance provisions.

Novartis announced in July that EP2006 was the first 351(k) application accepted for review by FDA, an event that occurred almost 4 12 years after passage of the BPCIA. Neupogen was first approved in February 1991 and is a relatively simple biologic, checking in at 175 amino acids. Amgen sold about $1.2B of Neupogen last year. Novartis, which claims world leadership in the biosimilar market, currently sells biosimilar filgrastim (as Zarzio) in over 40 countries. It is one of 19 approved biosimilars in Europe, where it was approved in February 2009 (EMA Public summary).

In advance of the advisory committee meeting, Novartis announced in December the results from Pioneer, its Phase 3 study of 218 patients. According to Novartis, Pioneer demonstrated EP2006’s similarity to Neupogen in the prevention of severe neutropenia in breast cancer patients. Novartis also said that the study showed that repeated switching at each cycle between the biosimilar and reference filgrastim showed no impact on efficacy, safety or immunogenicity.

As is customary, the Advisory Committee meeting was preceded by FDA’s release of a briefing document. The briefing document states that the analytical data show that both clinical and commercial lots of the Novartis product are “highly similar” to Neupogen notwithstanding “minor differences in clinically active components.” FDA also stated that the clinical development program showed that "there are no clinically meaningful differences” between EP2006 (Novartis’s internal name for its product) and Neupogen in terms of safety, purity and potency.” FDA specifically cited five PK and PD studies in healthy subjects and the Pioneer study. Of particular note, FDA discussed in the briefing document that commercial lots of EP2006 had a lower protein content than Neupogen, an issue that did not occur with the EP2006 clinical study lots. FDA also referenced Novartis’s use of EU-approved Neupogen in some clinical studies and the comparability studies submitted by the company to support the use of non-US product.

FDA added eight temporary members to the roster of the Oncologic Drugs Advisory Committee for this meeting, including the chief of the cell processing section of NIH’s Clinical Center, a biochemical engineer, a pharmaceutical sciences expert and a pharmacology expert. Given the reliance on analytical as well as clinical data to support biosimilar approval, this is not surprising.

As reflected in the unanimous votes on the questions raised by FDA, the Advisory Committee ultimately had relatively few concerns about the safety and efficacy of EP2006. The issue of pricing was, however, raised by several committee members, and questioning of one Novartis employee led to an assurance that the product would cost less than Neupogen (see New York Times article here).

The issues that were not raised in the briefing document and at the meeting are worth noting. One prominent one is of course whether the Novartis product will have the generic name filgrastim or some variant. Another issue for Novartis is that its proposed brand name, Zarxio, has apparently not yet been accepted by FDA. Without either a settled generic or brand name, the internal reference EP2006 was used throughout the meeting and in the briefing document. There was also no mention at all of interchangeability, governed by a higher standard than simple biosimilarity.

Assuming that FDA accepts its advisory committee’s recommendation and moves on to approval, EP2006 faces another big challenge before it gets to the market. Novartis and Amgen are locked in patent litigation that has raised the issue of whether and how the complicated patent dance provisions of the BPCIA applies (see our previous posts here, here, here and here). Amgen recently fled a Motion for Partial Summary Judgment in the case. The issue that has spilled over into an FDA citizen petition (see our previous post here). And patent dance applicability reared its head on another front last week as Momenta supplemented its 2012 comments to an Amgen citizen petition that requests FDA to declare that the patent dance provisions are mandatory (see comments here).

One other event last week illustrates the less than smooth road ahead for biosimilars. FDA announced that it plans to issue four more biosimilar guidances in 2015, covering interchangeability, labeling, statistical issues, and additional general questions and answers.